OVERALL SUMMARY/ABSTRACT This Case GI SPORE renewal application provides for a cutting edged Specialized Program of Research Excellence in gastrointestinal malignancies with emphasis on colorectal cancers and adenocarcinoma of the esophagus. This comprehensive program builds on the resources of the Case Comprehensive Cancer Center to propose 4 translational Research Projects to bring new molecular advances to patients with GI Cancers. A series of 3 core resources support these projects and also establish a strong programmatic infrastructure for translational research in GI cancers. We have further developed a comprehensive infrastructure for identifying new Developmental Research Projects from basic science and clinical investigators from across the Case Cancer Center. Drawing on our strong track record of developing new faculty who emphasize translational research in GI cancers, we have also developed a targeted Career Enhancement Program to further advance and recruit to the translational research cadre of SPORE faculty. The 4 SPORE translational research projects constitute novel and cutting edge approaches to GI cancers and include studies of: i) Targeting the 15-PGDH colon cancer tumor suppressor pathway for prediction of cancer risk, prediction of response to chemoprevention with aspirin, and development of new colon cancer prevention and treatment strategies (Project 1, Drs. Markowitz, Li, and Berger); ii) Elucidating the basis for and the clinical significance of a mutational signature of African American colon cancer (Project 2, Drs. Willis, Li, and Wang); iii) Development of molecular markers of and non-endoscopic detection of Barrett's esophagus and early esophageal adenocarcinomas (Project 3, Drs. Chak, Guda, and Markowitz); and iv) Development of personalized treatment of PIK3CA mutant colon cancers using targeted inhibitors of glutamine metabolism (Project 4, Drs. Wang and Meropol). These projects are built on major advances from the SPORE's first funding period that include: i) publication in Science that 15-PGDH regulates colon crypt stem cells; ii) publication in Science Translational Medicine that individual's 15-PGDH levels regulate whether taking aspirin will or will not reduce their colon cancer risk; iii) publication in Proceedings of the National Academy of Sciences of genes preferentially targeted for somatic mutations in colorectal cancers of African Americans; iv) publication on the cover of Cancer Epidemiology, Biomarkers and Prevention that testing for methylated vimentin DNA in esophageal brushings could detect over 90% of Barrett's esophagus and esophageal adenocarcinomas; v) publication in Nature Communications that PIK3CA mutant cancers are addicted to glutamine and sensitive to inhibitors of glutamine metabolism. These projects are advantaged by special populations and scientific resources developed for evaluation of GI cancer biomarkers, new drug discovery, Next-Generation sequencing of formalin fixed tumor samples, and studies of Barrett's esophagus. The strength of these investigators and the resources at their disposal will insure this program leads to significant important translational advances.